Clinical Implications of Novel Biomarkers of Hepatitis B Virus

Abstract

Conventional biomarkers for hepatitis B virus (HBV) infection include HBsAg, HBeAg and HBV DNA. All these markers have been standardized and utilized for many decades. Their importance in defining and managing HBV infection are well characterized. They are particularly useful in the disease prognostication and assessment treatment efficacy. In spite of the profound viral suppressive effects from nucleos(t)ide analogues (NA), their roles in particular, the serum HBV DNA levels become relatively limited in reflecting the intrahepatic total HBV DNA and cccDNA content. Furthermore, reliable markers predicting viral rebound after cessation of long-term NA therapy are lacking. In recent years, measurements of two novel HBV markers have been actively explored, with the aim of providing better correlations with regard to the disease activity and treatment outc ome. They are hepatitis B core-related antigen (HBcrAg) and HBV RNA. HBcrAg is a composite measurement of three viral proteins from pre-core/core gene transcription. They are HBcAg, HBeAg and p22cr. It has been found that HBcrAg has a strong correlation with intrahepatic cccDNA level even in patients with undetectable serum HBV DNA. In addition, HBcrAg has clinical significance in different scenarios of HBV disease including its reduction in levels during NA treatment, detectability in patients with HBsAg seroclearance, development of cirrhosis and HCC, and HBV reactivations from cessation of treatment and from occult HBV infected patients undergoing immunosuppressive therapy. HBV RNA is another new HBV marker being actively explored in different aspects of HBV infection. Pregenomic HBV RNA acts as the template for reverse transcription to relaxed circular DNA after encapsidation. HBV RNA levels are therefore detectable in the majority of HBV patients and possess distinct profiles in different disease phases. Serum HBV RNA levels are usually lower than that of serum HBV DNA. It has been shown to have good correlations with serum HBV DNA and intrahepatic cccDNA especially in HBeAg positive patients. NA treatment was shown to have suppressive effect on HBV RNA levels. Novel treatments targeting HBV RNA knockdown had also shown decrease in HBV RNA levels. In addition, detectable HBV RNA was associated with a higher chance of HCC development and also HBV relapse after cessation of the NA treatment. It is expected that measurements of these two new markers would provide more insightful information for clinicians to have better disease prognostication and management for HBV disease.